Bone Disease in Myeloma

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1 Bone Disease in Myeloma Boston, Massachusetts Saturday, July 26, 2008 Brian G.M. Durie, M.D.

2 Bone Disease in Myeloma Lytic Lesions Spike Bone Marrow Plasma Cells Collapse of Vertebrae

3 Biology of Myeloma Vascular Cytokines Lymphocytes/ Macrophages/ Hormones Hematopoietic Cells/ DNA/ RNA Chemicals Myeloma Cells Microbes Microenvironment Neuro Nor-adrenaline Bone osteoclasts/ osteoblasts/ matrix Other organs Liver/ lymphatic/ brain

Myeloma Cells Microbes Microenvironment Neuro Nor-adrenaline

4 Micro Environment and Bone Biology Systemic 1GF1 Osteoblasts Cells Matrix Local Blood Vessels

5 Bone Lesions in Myeloma 80% of patients have: Lytic lesions and/or Diffuse osteoporosis Bone lesions cause: Pain Fractures Pressure on nerves/spine Increase in blood calcium

6 Diagnosis of Bone Lesions X-ray: full skeletal survey CT scan or MRI with gadolinium* Bone density Whole body FDG/PET with CT and SUV assessment Bone turnover studies, e.g. NTX * Caution required with gadolinium

Whole body FDG/PET with CT and SUV assessment Bone

7 Bone Disease Classification Based upon Focal Lesions on X-ray and/or MRI

8 Staging With FDG-PET and CT FL on PET & MRI: Multiple Myeloma FDG PET: Severe Diffuse (D) and Focal (F) Disease F F D D F D D D D F FDG PET scan of thoracic spine MRI STIR weighted of thoracic spine

9 Serial PET Shows Early Response X-ray January JAN APRIL JUNE M-protein MRI November T1 STIR January April

10 MRI-CR lags Behind Clinical Response 100% Incidence of ncr/cr and Incidence of MRI-CR Patients with PET 1+ Shows Baseline Earlier FL detectable Evidence by of PET Response and by MRI 80% 60% PET & actual MRI 40% 20% MRI-CR ncr/cr Events / N 12 / / 59 P< Month Estimate 17% 61% 0% Months After Starting VAD * Walker, et al ASH

by MRI 80% 60% PET & actual MRI 40% 20% MRI-CR ncr/cr Events / N 12 / 59 33 / 59 P<0.

11 Treatment for Bone Disease Treat the myeloma Chemotherapy Radiation Treat the bone Bisphosphonates Calcium/Vitamin D Supportive care Kyphoplasty

12 Bisphosphonates Primary Therapy for myeloma bone disease to reduce skeletal related events (SREs) Recommended as ongoing therapy for all myeloma patients with bone disease

13 Bisphosphonate Use Guidelines 2007 Mayo/ IMF Perspectives* Starting BP Duration of therapy Choice of BP Renal l issues Dental evaluation *SEE: Mayo Clinic Proceedings, 82(4); April 2007

14 Starting Bisphosphonates Lesions on x-ray Positive findings on MRI and/or CT PET MRI: > 7 lesions and/or progression/ pain PET: high SUV; CT abnormal Reduced d bone mineral activity? it Increased bone turnover? Not smoldering

progression/ pain PET: high SUV; CT abnormal Reduced d

15 Duration of Bisphosphonates Not indefinite Minimum 2 years Can consider stopping early if > VGPR AND No active bone disease Stop* at 2 years if no active bone disease Restart if new disease *Every 3 months also an option.

active bone disease Stop* at 2 years if no active bone

16 Stopping versus Reduced Dose/ Schedule Consider both renal/ ONJ issues No data on Q2 or 3 months Clinical trials needed

17 Choice of Bisphosphonate Consensus that efficacy equivalent (S.R.E.s) for available BPs: Pamidronate; Clodronate; Zoledronic acid. Concern that there is higher risk of toxicities with Zometa Jaw osteonecrosis major concern Jaw osteonecrosis major concern, but renal toxicity also greater.

Concern that there is higher risk of toxicities with Zometa Jaw

18 Current Bisphosphonates Aredia 90 mg over 2-4 hrs. monthly Zometa 4 mg over minutes monthly Questions: Infusion times Long term duration/ schedule

19 Osteonecrosis of Jaw on Panorex

20 How Frequent is Osteonecrosis? Rare prior to Marx reported 36 patients [JOMF SURG 61: ] 2004 Ruggiero, et al reported 63 patients diagnosed dag [JOMF SURG 62: ] Durie, et al reported 75 patients from IMF survey [NEJM July 7 th, 2005] : 4% for Aredia; 10% for Zometa 2005 Groups from US, Italy, Greece and elsewhere document bisphosphonate p associated osteonecrosis (BAO). M.D. Anderson 4.5% [J. Bon Min Res 20(1) 555; ] Greece 99% 9.9% [JCO 23: ]

dag 2001-2003 003 [JOMF SURG 62:527 2004] Durie, et al reported 75 patients from IMF survey [NEJM July 7 th, 2005] : 4% for

21 How frequent is osteonecrosis? (Continued) 2007 Now total of 26 case reports and 13 case series (120 cases) evaluating bisphosphonate associated osteonecrosis [Krieger, et al. The Annuals of Pharmacotherapy 41: ] ONJ more common with Zometa ONJ >6-7% at 2 years Additional risk factors under investigation, including: Diabetes mellitus [Khamaisi, et al. J. Clin Endocrinol Metab 92: ] Oxidative stress; bone remodeling factors New report from Germany: ONJ 3.5 times higher with Zometa [Boonyapakorn et al Oral Onc. Feb 2008]

22 20% Time to Onset of Osteonecrosis in Myeloma Zometa vs Aredia 25% 36-Month Events / N Estimate Zometa 10 / % P =.002 Aredia 10 / 413 4% 15% Data censored at 36 months 10% 5% 0% Months from start of Aredia or Zometa

23 Management Recommendations for ONJ Before starting bisphosphonates (BP) Dental evaluation/ treatment While On BP Regular dental care/ check-ups Avoid dental extraction/ procedures Review type/ schedule of BP with MD? Reduce Frequency or take drug holiday ld Established ONJ Antibiotics Minor dental procedures Rinses/ supportive measures Stop BP Rx to allow healing Possible hyperbaric 0 2

24 New Approaches to Enhance Osteoblast Activity and Heal Bones Denusomab (Amgen) MIP 1 α modulation DKK 1 protein inhibition VELCADE Cholesterol lowering statins, e.g. Lipitor Quadramet (Samarium)

25 Overall Strategies Diagnose & monitor bone disease Take bisphosphonate therapy with good monitoring Exercise Get pain relief Avoid risky situations

Bone Disease in Myeloma

Bone Disease in Myeloma Washington, DC August 8, 2009 Brian G.M. Durie, M.D. Bone Disease in Myeloma Lytic Lesions Spike Bone Marrow Plasma Cells Collapse of Vertebrae Biology of Myeloma Vascular Cytokines